Abstract:
:Cancer clinics currently use high-dose stereotactic body radiation therapy as a curative treatment for several kinds of cancers. However, the contribution of vascular endothelial cells to tumor response to radiation remains controversial. Using dual recombinase technology, we generated primary sarcomas in mice with targeted genetic mutations specifically in tumor cells or endothelial cells. We selectively mutated the proapoptotic gene Bax or the DNA damage response gene Atm to genetically manipulate the radiosensitivity of endothelial cells in primary soft tissue sarcomas. Bax deletion from endothelial cells did not affect radiation-induced cell death in tumor endothelial cells or sarcoma response to radiation therapy. Although Atm deletion increased endothelial cell death after radiation therapy, deletion of Atm from endothelial cells failed to enhance sarcoma eradication. In contrast, deletion of Atm from tumor cells increased sarcoma eradication by radiation therapy. These results demonstrate that tumor cells, rather than endothelial cells, are critical targets that regulate sarcoma eradication by radiation therapy. Treatment with BEZ235, a small-molecule protein kinase inhibitor, radiosensitized primary sarcomas more than the heart. These results suggest that inhibiting ATM kinase during radiation therapy is a viable strategy for radiosensitization of some tumors.
journal_name
Sci Transl Medjournal_title
Science translational medicineauthors
Moding EJ,Castle KD,Perez BA,Oh P,Min HD,Norris H,Ma Y,Cardona DM,Lee CL,Kirsch DGdoi
10.1126/scitranslmed.aaa4214subject
Has Abstractpub_date
2015-03-11 00:00:00pages
278ra34issue
278eissn
1946-6234issn
1946-6242pii
7/278/278ra34journal_volume
7pub_type
杂志文章abstract::Biomedical engineering tools can be harnessed to address some of the world's most challenging nondisease-focused problems. ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3009067
更新日期:2014-12-10 00:00:00
abstract::Chemotherapy-induced cardiotoxicity (CIC) is a common clinical problem that compromises effective anticancer therapies. Many chemotherapeutics (including anthracyclines, such as doxorubicin) induce the proapoptotic transcription factor p53 in the tumor and nonspecifically in the heart, promoting heart failure. Althoug...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aau8866
更新日期:2019-02-06 00:00:00
abstract::A clinical trial evaluating HIV vaccine therapy teaches us much about optimal design (Sneller et al, this issue). ...
journal_title:Science translational medicine
pub_type: 杂志文章,评审
doi:10.1126/scitranslmed.aaq0810
更新日期:2017-12-06 00:00:00
abstract::Hutchinson-Gilford progeria syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates a cryptic donor splice site and yields a truncated form of prelamin A called progerin. Small amounts of progerin are also produced during normal aging. Studies with mouse models of HGPS have allowed the recent dev...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3002847
更新日期:2011-10-26 00:00:00
abstract::An analysis of four regions in four countries suggests that the best way to mitigate disruption of the pharmaceutical industry is not to ignore or stem it but to sponsor initiatives that keep scientists engaged. ...
journal_title:Science translational medicine
pub_type: 杂志文章,评审
doi:10.1126/scitranslmed.aaa3679
更新日期:2015-05-06 00:00:00
abstract::Previous attempts to gain insight into the pathogenesis of psoriasis and eczema by comparing their molecular signatures were hampered by the high interindividual variability of those complex diseases. In patients affected by both psoriasis and nonatopic or atopic eczema simultaneously (n = 24), an intraindividual comp...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3008946
更新日期:2014-07-09 00:00:00
abstract::Direct-to-consumer (DTC) advertising of suspect goods and services has burgeoned because of the Internet. Despite very limited approval for use, DTC stem cell-marketed "treatments" have emerged for an array of conditions, creating global public health and safety risks. However, it remains unclear whether such use of s...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3004030
更新日期:2012-09-12 00:00:00
abstract::Cooperative oncogenic effects resulting from the loss of PTEN and overexpression of MYC overcome the deleterious effects of endoplasmic reticulum stress not only to promote the growth of aggressive prostate cancer but also to expose a new therapy target for this disease (Nguyen et al, this issue). ...
journal_title:Science translational medicine
pub_type: 杂志文章,评审
doi:10.1126/scitranslmed.aat3975
更新日期:2018-05-02 00:00:00
abstract::A primary barrier to the success of T cell-recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, we developed an anti-HER2/CD3 T cell-dependent b...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aat5775
更新日期:2018-10-17 00:00:00
abstract::Nonalcoholic fatty liver disease (NAFLD) is estimated to affect up to one-third of the general population, and new therapies are urgently required. Our laboratory previously developed a controlled-release mitochondrial protonophore (CRMP) that is functionally liver-targeted and promotes oxidation of hepatic triglyceri...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aay0284
更新日期:2019-10-02 00:00:00
abstract::Cardiac rhythm is extremely robust, generating 2 billion contraction cycles during the average human life span. Transcriptional control of cardiac rhythm is poorly understood. We found that removal of the transcription factor gene Tbx5 from the adult mouse caused primary spontaneous and sustained atrial fibrillation (...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaf4891
更新日期:2016-08-31 00:00:00
abstract::The AAA+ adenosine triphosphatase (ATPase) Thorase plays a critical role in controlling synaptic plasticity by regulating the expression of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Bidirectional sequencing of exons of ATAD1, the gene encoding Thorase, in a cohort of patients wit...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aah4985
更新日期:2017-12-13 00:00:00
abstract::Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous hematological malignancy. Although immunotherapy may be an attractive modality to exploit in patients with AML, the ability to predict the groups of patients and the types of cancer that will respond to immune targeting remains limited. This st...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaz0463
更新日期:2020-06-03 00:00:00
abstract::Touch perception on the fingers and hand is essential for fine motor control, contributes to our sense of self, allows for effective communication, and aids in our fundamental perception of the world. Despite increasingly sophisticated mechatronics, prosthetic devices still do not directly convey sensation back to the...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3008669
更新日期:2014-10-08 00:00:00
abstract::As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aad9735
更新日期:2017-04-26 00:00:00
abstract::Despite the existence of effective rabies vaccines for dogs, dog-transmitted human rabies persists and has reemerged in Africa. Two consecutive dog vaccination campaigns took place in Chad in 2012 and 2013 (coverage of 71% in both years) in the capital city of N'Djaména, as previously published. We developed a determi...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaf6984
更新日期:2017-12-20 00:00:00
abstract::The brain is emerging as an important regulator of systemic glucose metabolism. Accumulating data from animal and observational human studies suggest that striatal dopamine signaling plays a role in glucose regulation, but direct evidence in humans is currently lacking. We present a series of experiments supporting th...
journal_title:Science translational medicine
pub_type: 杂志文章,随机对照试验
doi:10.1126/scitranslmed.aar3752
更新日期:2018-05-23 00:00:00
abstract::As observed during the 2013-2016 Ebola virus disease epidemic, containment of filovirus outbreaks is challenging and made more difficult by the lack of approved vaccine or therapeutic options. Marburg and Ravn viruses are highly virulent and cause severe and frequently lethal disease in humans. Monoclonal antibodies (...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aai8711
更新日期:2017-04-05 00:00:00
abstract::Gene replacement and pre-mRNA splicing modifier therapies represent breakthrough gene targeting treatments for the neuromuscular disease spinal muscular atrophy (SMA), but mechanisms underlying variable efficacy of treatment are incompletely understood. Our examination of severe infantile onset human SMA tissues obtai...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.abb6871
更新日期:2021-01-27 00:00:00
abstract::More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aad5169
更新日期:2016-01-20 00:00:00
abstract::Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived fro...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaf3962
更新日期:2017-05-24 00:00:00
abstract::Attention deficit hyperactivity disorder (ADHD) is a common and persistent condition characterized by developmentally atypical and impairing inattention, hyperactivity, and impulsiveness. We identified de novo and rare copy number variations (CNVs) in 248 unrelated ADHD patients using million-feature genotyping arrays...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3002464
更新日期:2011-08-10 00:00:00
abstract::Three-dimensional (3D) titanium-mesh scaffolds offer many advantages over autologous bone grafting for the regeneration of challenging large segmental bone defects. Our study supports the hypothesis that endogenous bone defect regeneration can be promoted by mechanobiologically optimized Ti-mesh scaffolds. Using finit...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aam8828
更新日期:2018-01-10 00:00:00
abstract::Elucidating the factors that impinge on the stability of bacterial communities in the vagina may help in predicting the risk of diseases that affect women's health. Here, we describe the temporal dynamics of the composition of vaginal bacterial communities in 32 reproductive-age women over a 16-week period. The analys...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3003605
更新日期:2012-05-02 00:00:00
abstract::A rare neurodevelopmental disorder in the Old Order Mennonite population called PMSE (polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome; also called Pretzel syndrome) is characterized by infantile-onset epilepsy, neurocognitive delay, craniofacial dysmorphism, and histopathological evidence of heteroto...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3005271
更新日期:2013-04-24 00:00:00
abstract::As the prevalence of Alzheimer's disease (AD) grows, so do the costs it imposes on society. Scientific, clinical, and financial interests have focused current drug discovery efforts largely on the single biological pathway that leads to amyloid deposition. This effort has resulted in slow progress and disappointing ou...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3008228
更新日期:2014-06-18 00:00:00
abstract::Epithelial tissues line the organs of the body, providing an initial protective barrier as well as a surface for nutrient and drug absorption. Here, we identified enzymatic components present in the gastrointestinal epithelium that can serve as selective means for tissue-directed polymerization. We focused on the smal...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.abc0441
更新日期:2020-08-26 00:00:00
abstract::The efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by acute and chronic graft-versus-host disease (GVHD). The impact of obesity on allo-HSCT outcomes is poorly understood. Here, we report that obesity had a negative and selective impact on acute gut GVHD after allo-HSCT in mice w...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aay7713
更新日期:2020-11-25 00:00:00
abstract::Each year, more than a half million people in the United States alone die from sepsis, a dire multisystem disease with highly inadequate treatment options. In a recent issue of Science, Puneet and colleagues provide compelling evidence that inhibiting sphingosine kinase 1--an enzyme that resides in immune cells and is...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3001299
更新日期:2010-06-16 00:00:00
abstract::Current HIV vaccines are only partially efficacious, presenting an opportunity to identify correlates of protection and, thereby, potential insight into mechanisms that prevent HIV acquisition. Two independent preclinical challenge studies in nonhuman primates (NHPs) previously showed partial efficacy of a mosaic aden...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaw4236
更新日期:2019-08-28 00:00:00